Molecular basis for multimerization in the activation of the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that...

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Main Authors:	Yongjian Huang, Shashank Bharill, Deepti Karandur, Sean M Peterson, Morgan Marita, Xiaojun Shi, Megan J Kaliszewski, Adam W Smith, Ehud Y Isacoff, John Kuriyan
Format:	Article
Language:	English
Published:	eLife Sciences Publications Ltd 2016-03-01
Series:	eLife
Subjects:	EGFR stoichiometry multimerization
Online Access:	https://elifesciences.org/articles/14107

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spelling	doaj-20dcaaea62014192b2103042c99e3e7a2021-06-22T10:05:18ZengeLife Sciences Publications LtdeLife2050-084X2016-03-01510.7554/eLife.14107Molecular basis for multimerization in the activation of the epidermal growth factor receptorYongjian Huang0Shashank Bharill1Deepti Karandur2Sean M Peterson3Morgan Marita4Xiaojun Shi5Megan J Kaliszewski6Adam W Smith7Ehud Y Isacoff8https://orcid.org/0000-0003-4775-9359John Kuriyan9https://orcid.org/0000-0002-4414-5477Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Biophysics Graduate Group, University of California, Berkeley, Berkeley, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United StatesDepartment of Chemistry, University of Akron, Akron, United StatesDepartment of Chemistry, University of Akron, Akron, United StatesDepartment of Chemistry, University of Akron, Akron, United StatesDepartment of Chemistry, University of Akron, Akron, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United StatesDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United StatesThe epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation.https://elifesciences.org/articles/14107EGFRstoichiometrymultimerization
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Yongjian Huang Shashank Bharill Deepti Karandur Sean M Peterson Morgan Marita Xiaojun Shi Megan J Kaliszewski Adam W Smith Ehud Y Isacoff John Kuriyan
spellingShingle	Yongjian Huang Shashank Bharill Deepti Karandur Sean M Peterson Morgan Marita Xiaojun Shi Megan J Kaliszewski Adam W Smith Ehud Y Isacoff John Kuriyan Molecular basis for multimerization in the activation of the epidermal growth factor receptor eLife EGFR stoichiometry multimerization
author_facet	Yongjian Huang Shashank Bharill Deepti Karandur Sean M Peterson Morgan Marita Xiaojun Shi Megan J Kaliszewski Adam W Smith Ehud Y Isacoff John Kuriyan
author_sort	Yongjian Huang
title	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_short	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_full	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_fullStr	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_full_unstemmed	Molecular basis for multimerization in the activation of the epidermal growth factor receptor
title_sort	molecular basis for multimerization in the activation of the epidermal growth factor receptor
publisher	eLife Sciences Publications Ltd
series	eLife
issn	2050-084X
publishDate	2016-03-01
description	The epidermal growth factor receptor (EGFR) is activated by dimerization, but activation also generates higher-order multimers, whose nature and function are poorly understood. We have characterized ligand-induced dimerization and multimerization of EGFR using single-molecule analysis, and show that multimerization can be blocked by mutations in a specific region of Domain IV of the extracellular module. These mutations reduce autophosphorylation of the C-terminal tail of EGFR and attenuate phosphorylation of phosphatidyl inositol 3-kinase, which is recruited by EGFR. The catalytic activity of EGFR is switched on through allosteric activation of one kinase domain by another, and we show that if this is restricted to dimers, then sites in the tail that are proximal to the kinase domain are phosphorylated in only one subunit. We propose a structural model for EGFR multimerization through self-association of ligand-bound dimers, in which the majority of kinase domains are activated cooperatively, thereby boosting tail phosphorylation.
topic	EGFR stoichiometry multimerization
url	https://elifesciences.org/articles/14107
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Molecular basis for multimerization in the activation of the epidermal growth factor receptor

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